Photo of Bradley E. Bernstein,  MD, PhD

Bradley E. Bernstein, MD, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 726-6906
Fax: (617) 643-3566


bernstein.bradley@mgh.harvard.edu

Bradley E. Bernstein, MD, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Professor, Pathology, Harvard Medical School
  • Pathologist , Pathology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

Professor of Pathology at Harvard Medical School, Early Career Scientist at Howard Hughes Medical Institute and Senior Associate Member at the Broad Institute. Laboratory in the Richard B. Simches Research Building at Massachusetts General Hospital, part of Experimental Pathology and the Center of Systems Biology with research focused on chromatin and epigenetic regulation in normal and malignant stem cells. The laboratory applies high-throughput genomic technologies to study the role of chromatin in the regulation of cell fates, functional phenotypes and drug sensitivity. The group has introduced new technologies for mapping chromatin structure genome-wide and for locus-specific editing of chromatin modifications. Notable biological findings include the identification of alternative types of large-scale chromatin structures, or ‘domains’, that maintain gene activity, gene repression or gene potential under specific cellular contexts. For example, in differentiated cells, chromatin domains marked by either ‘active’ or ‘repressive’ histone modifications maintain expression or repression of key developmental genes. However, in pluripotent ES cells, ‘bivalent’ domains enriched for both active and repressive modifications keep developmental genes poised for subsequent activation. Current projects in the lab are focused on understanding the structures, functions and mechanisms of bivalent' domains and other chromatin states in developing stem cells. Towards this end we are deploying new technologies for profiling chromatin at single molecule and single cell resolution, and for global and locus-specific perturbation of chromatin structure. Analogous approaches are now being applied to characterize aberrant chromatin states and regulatory circuits that underlie malignant phenotypes and drug resistance in tumor models, including glioblastoma, leukemia and other cancers.

Publications

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  • Karaayvaz M, Cristea S, Gillespie SM, Patel AP, Mylvaganam R, Luo CC, Specht MC, Bernstein BE, Michor F, Ellisen LW. Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq. Nat Commun 2018; 9:3588. PubMed
  • Santos-Rosa H, Schneider R, Bernstein BE, Karabetsou N, Morillon A, Weise C, Schreiber SL, Mellor J, Kouzarides T. Methylation of Histone H3 K4 Mediates Association of the Isw1p ATPase with Chromatin. Mol Cell 2018; 70:983. PubMed
  • Finucane HK, Reshef YA, Anttila V, Slowikowski K, Gusev A, Byrnes A, Gazal S, Loh PR, Lareau C, Shoresh N, Genovese G, Saunders A, Macosko E, Pollack S, , Perry JRB, Buenrostro JD, Bernstein BE, Raychaudhuri S, McCarroll S, Neale BM, Price AL. Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types. Nat Genet 2018; 50:621-629. PubMed
  • Kleppe M, Koche R, Zou L, van Galen P, Hill CE, Dong L, De Groote S, Papalexi E, Hanasoge Somasundara AV, Cordner K, Keller M, Farnoud N, Medina J, McGovern E, Reyes J, Roberts J, Witkin M, Rapaport F, Teruya-Feldstein J, Qi J, Rampal R, Bernstein BE, Bradner JE, Levine RL. Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell 2018; 33:29-43.e7. PubMed
  • Song KA, Niederst MJ, Lochmann TL, Hata AN, Kitai H, Ham J, Floros KV, Hicks MA, Hu H, Mulvey HE, Drier Y, Heisey DAR, Hughes MT, Patel NU, Lockerman EL, Garcia A, Gillepsie S, Archibald HL, Gomez-Caraballo M, Nulton TJ, Windle BE, Piotrowska Z, Sahingur SE, Taylor SM, Dozmorov M, Sequist LV, Bernstein B, Ebi H, Engelman JA, Faber AC. Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM. Clin Cancer Res 2018; 24:197-208. PubMed
  • Najm FJ, Strand C, Donovan KF, Hegde M, Sanson KR, Vaimberg EW, Sullender ME, Hartenian E, Kalani Z, Fusi N, Listgarten J, Younger ST, Bernstein BE, Root DE, Doench JG. Orthologous CRISPR-Cas9 enzymes for combinatorial genetic screens. Nat Biotechnol 2018. PubMed
  • Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, Rodman C, Luo CL, Mroz EA, Emerick KS, Deschler DG, Varvares MA, Mylvaganam R, Rozenblatt-Rosen O, Rocco JW, Faquin WC, Lin DT, Regev A, Bernstein BE. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell 2017; 171:1611-1624.e24. PubMed
  • Ryan RJH, Petrovic J, Rausch DM, Zhou Y, Lareau CA, Kluk MJ, Christie AL, Lee WY, Tarjan DR, Guo B, Donohue LKH, Gillespie SM, Nardi V, Hochberg EP, Blacklow SC, Weinstock DM, Faryabi RB, Bernstein BE, Aster JC, Pear WS. A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas. Cell Rep 2017; 21:784-797. PubMed
  • Rao SSP, Huang SC, Glenn St Hilaire B, Engreitz JM, Perez EM, Kieffer-Kwon KR, Sanborn AL, Johnstone SE, Bascom GD, Bochkov ID, Huang X, Shamim MS, Shin J, Turner D, Ye Z, Omer AD, Robinson JT, Schlick T, Bernstein BE, Casellas R, Lander ES, Aiden EL. Cohesin Loss Eliminates All Loop Domains. Cell 2017; 171:305-320.e24. PubMed
  • Shah N, Wang P, Wongvipat J, Karthaus WR, Abida W, Armenia J, Rockowitz S, Drier Y, Bernstein BE, Long HW, Freedman ML, Arora VK, Zheng D, Sawyers CL. Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer. Elife 2017. PubMed
  • Gupta RM, Hadaya J, Trehan A, Zekavat SM, Roselli C, Klarin D, Emdin CA, Hilvering CRE, Bianchi V, Mueller C, Khera AV, Ryan RJH, Engreitz JM, Issner R, Shoresh N, Epstein CB, de Laat W, Brown JD, Schnabel RB, Bernstein BE, Kathiresan S. A Genetic Variant Associated with Five Vascular Diseases Is a Distal Regulator of Endothelin-1 Gene Expression. Cell 2017; 170:522-533.e15. PubMed
  • Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science 2017. PubMed
  • Miller TE, Liau BB, Wallace LC, Morton AR, Xie Q, Dixit D, Factor DC, Kim LJY, Morrow JJ, Wu Q, Mack SC, Hubert CG, Gillespie SM, Flavahan WA, Hoffmann T, Thummalapalli R, Hemann MT, Paddison PJ, Horbinski CM, Zuber J, Scacheri PC, Bernstein BE, Tesar PJ, Rich JN. Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 2017. PubMed
  • Liau BB, Sievers C, Donohue LK, Gillespie SM, Flavahan WA, Miller TE, Venteicher AS, Hebert CH, Carey CD, Rodig SJ, Shareef SJ, Najm FJ, van Galen P, Wakimoto H, Cahill DP, Rich JN, Aster JC, Suvà ML, Patel AP, Bernstein BE. Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance. Cell Stem Cell 2016. PubMed
  • Grossman SR, Zhang X, Wang L, Engreitz J, Melnikov A, Rogov P, Tewhey R, Isakova A, Deplancke B, Bernstein BE, Mikkelsen TS, Lander ES. Systematic dissection of genomic features determining transcription factor binding and enhancer function. Proc Natl Acad Sci U S A 2017. PubMed
  • Wang X, Lee RS, Alver BH, Haswell JR, Wang S, Mieczkowski J, Drier Y, Gillespie SM, Archer TC, Wu JN, Tzvetkov EP, Troisi EC, Pomeroy SL, Biegel JA, Tolstorukov MY, Bernstein BE, Park PJ, Roberts CW. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet 2016. PubMed
  • Venteicher AS, Tirosh I, Hebert C, Escalante L, Martuza RL, Nahed BV, Curry WT, Cahill DP, Bernstein B, Louis DN, Regev A, Suva M. 142 Genetic and Nongenetic Determinants of Cellular Architecture in IDH1-Mutant Oligodendrogliomas and Astrocytomas Using Single-Cell Transcriptome Analysis. Neurosurgery 2016; 63 Suppl 1:158. PubMed
  • Xie Q, Wu Q, Kim L, Miller TE, Liau BB, Mack SC, Yang K, Factor DC, Fang X, Huang Z, Zhou W, Alazem K, Wang X, Bernstein BE, Bao S, Rich JN. RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. J Clin Invest 2016; 126:2757-72. PubMed
  • Shema E, Jones D, Shoresh N, Donohue L, Ram O, Bernstein BE. Single-molecule decoding of combinatorially modified nucleosomes. Science 2016; 352:717-21. PubMed
  • Drier Y, Cotton MJ, Williamson KE, Gillespie SM, Ryan RJ, Kluk MJ, Carey CD, Rodig SJ, Sholl LM, Afrogheh AH, Faquin WC, Queimado L, Qi J, Wick MJ, El-Naggar AK, Bradner JE, Moskaluk CA, Aster JC, Knoechel B, Bernstein BE. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat Genet 2016. PubMed
  • Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 2016; 529:110-4. PubMed
  • van Galen P, Viny AD, Ram O, Ryan RJ, Cotton MJ, Donohue L, Sievers C, Drier Y, Liau BB, Gillespie SM, Carroll KM, Cross MB, Levine RL, Bernstein BE. A Multiplexed System for Quantitative Comparisons of Chromatin Landscapes. Mol Cell 2016; 61:170-80. PubMed
  • Rotem A, Ram O, Shoresh N, Sperling RA, Goren A, Weitz DA, Bernstein BE. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat Biotechnol 2015; 33:1165-72. PubMed
  • Renneville A, Van Galen P, Canver MC, McConkey M, Krill-Burger JM, Dorfman DM, Holson EB, Bernstein BE, Orkin SH, Bauer DE, Ebert BL. EHMT1 and EHMT2 inhibition induces fetal hemoglobin expression. Blood 2015. PubMed
  • Ryan RJ, Drier Y, Whitton H, Cotton MJ, Kaur J, Issner R, Gillespie S, Epstein CB, Nardi V, Sohani AR, Hochberg EP, Bernstein BE. Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma. 2015; 5:1058-71. PubMed
  • , Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M. Integrative analysis of 111 reference human epigenomes. Nature 2015; 518:317-30. PubMed
  • Ziller MJ, Edri R, Yaffe Y, Donaghey J, Pop R, Mallard W, Issner R, Gifford CA, Goren A, Xing J, Gu H, Cacchiarelli D, Tsankov AM, Epstein C, Rinn JL, Mikkelsen TS, Kohlbacher O, Gnirke A, Bernstein BE, Elkabetz Y, Meissner A. Dissecting neural differentiation regulatory networks through epigenetic footprinting. Nature 2015; 518:355-9. PubMed
  • Farh KK, Marson A, Zhu J, Kleinewietfeld M, Housley WJ, Beik S, Shoresh N, Whitton H, Ryan RJ, Shishkin AA, Hatan M, Carrasco-Alfonso MJ, Mayer D, Luckey CJ, Patsopoulos NA, De Jager PL, Kuchroo VK, Epstein CB, Daly MJ, Hafler DA, Bernstein BE. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 2015; 518:337-43. PubMed
  • Rotem A, Ram O, Shoresh N, Sperling RA, Schnall-Levin M, Zhang H, Basu A, Bernstein BE, Weitz DA. High-Throughput Single-Cell Labeling (Hi-SCL) for RNA-Seq Using Drop-Based Microfluidics. PLoS ONE 2015; 10:e0116328. PubMed
  • Yashiro-Ohtani Y, Wang H, Zang C, Arnett KL, Bailis W, Ho Y, Knoechel B, Lanauze C, Louis L, Forsyth KS, Chen S, Chung Y, Schug J, Blobel GA, Liebhaber SA, Bernstein BE, Blacklow SC, Liu XS, Aster JC, Pear WS. Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia. Proc Natl Acad Sci U S A 2014; 111:E4946-53. PubMed
  • Riggi N, Knoechel B, Gillespie SM, Rheinbay E, Boulay G, Suvà ML, Rossetti NE, Boonseng WE, Oksuz O, Cook EB, Formey A, Patel A, Gymrek M, Thapar V, Deshpande V, Ting DT, Hornicek FJ, Nielsen GP, Stamenkovic I, Aryee MJ, Bernstein BE, Rivera MN. EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma. Cancer Cell 2014; 26:668-81. PubMed
  • Stoeck A, Lejnine S, Truong A, Pan L, Wang H, Zang C, Yuan J, Ware C, MacLean J, Garrett-Engele PW, Kluk M, Laskey J, Haines BB, Moskaluk C, Zawel L, Fawell S, Gilliland G, Zhang T, Kremer BE, Knoechel B, Bernstein BE, Pear WS, Liu XS, Aster JC, Sathyanarayanan S. Discovery of biomarkers predictive of GSI response in triple-negative breast cancer and adenoid cystic carcinoma. 2014; 4:1154-67. PubMed
  • Ho JW, Jung YL, Liu T, Alver BH, Lee S, Ikegami K, Sohn KA, Minoda A, Tolstorukov MY, Appert A, Parker SC, Gu T, Kundaje A, Riddle NC, Bishop E, Egelhofer TA, Hu SS, Alekseyenko AA, Rechtsteiner A, Asker D, Belsky JA, Bowman SK, Chen QB, Chen RA, Day DS, Dong Y, Dose AC, Duan X, Epstein CB, Ercan S, Feingold EA, Ferrari F, Garrigues JM, Gehlenborg N, Good PJ, Haseley P, He D, Herrmann M, Hoffman MM, Jeffers TE, Kharchenko PV, Kolasinska-Zwierz P, Kotwaliwale CV, Kumar N, Langley SA, Larschan EN, Latorre I, Libbrecht MW, Lin X, Park R, Pazin MJ, Pham HN, Plachetka A, Qin B, Schwartz YB, Shoresh N, Stempor P, Vielle A, Wang C, Whittle CM, Xue H, Kingston RE, Kim JH, Bernstein BE, Dernburg AF, Pirrotta V, Kuroda MI, Noble WS, Tullius TD, Kellis M, MacAlpine DM, Strome S, Elgin SC, Liu XS, Lieb JD, Ahringer J, Karpen GH, Park PJ. Comparative analysis of metazoan chromatin organization. Nature 2014; 512:449-52. PubMed
  • Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK, Ward LD, Birney E, Crawford GE, Dekker J, Dunham I, Elnitski LL, Farnham PJ, Feingold EA, Gerstein M, Giddings MC, Gilbert DM, Gingeras TR, Green ED, Guigo R, Hubbard T, Kent J, Lieb JD, Myers RM, Pazin MJ, Ren B, Stamatoyannopoulos J, Weng Z, White KP, Hardison RC. Reply to Brunet and Doolittle: Both selected effect and causal role elements can influence human biology and disease. Proc Natl Acad Sci U S A 2014; 111:E3366. PubMed
  • Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, Cahill DP, Nahed BV, Curry WT, Martuza RL, Louis DN, Rozenblatt-Rosen O, Suvà ML, Regev A, Bernstein BE. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014. PubMed
  • Attanasio C, Nord AS, Zhu Y, Blow MJ, Biddie SC, Mendenhall EM, Dixon J, Wright C, Hosseini R, Akiyama JA, Holt A, Plajzer-Frick I, Shoukry M, Afzal V, Ren B, Bernstein BE, Rubin EM, Visel A, Pennacchio LA. Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis. Genome Res 2014. PubMed
  • Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK, Ward LD, Birney E, Crawford GE, Dekker J, Dunham I, Elnitski LL, Farnham PJ, Feingold EA, Gerstein M, Giddings MC, Gilbert DM, Gingeras TR, Green ED, Guigo R, Hubbard T, Kent J, Lieb JD, Myers RM, Pazin MJ, Ren B, Stamatoyannopoulos JA, Weng Z, White KP, Hardison RC. Defining functional DNA elements in the human genome. Proc Natl Acad Sci U S A 2014. PubMed
  • Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV, Curry WT, Martuza RL, Rivera MN, Rossetti N, Kasif S, Beik S, Kadri S, Tirosh I, Wortman I, Shalek AK, Rozenblatt-Rosen O, Regev A, Louis DN, Bernstein BE. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 2014; 157:580-94. PubMed
  • Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ, Gillespie SM, Fernandez D, Ku M, Wang H, Piccioni F, Silver SJ, Jain M, Pearson D, Kluk MJ, Ott CJ, Shultz LD, Brehm MA, Greiner DL, Gutierrez A, Stegmaier K, Kung AL, Root DE, Bradner JE, Aster JC, Kelliher MA, Bernstein BE. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 2014; 46:364-70. PubMed
  • Maeder ML, Angstman JF, Richardson ME, Linder SJ, Cascio VM, Tsai SQ, Ho QH, Sander JD, Reyon D, Bernstein BE, Costello JF, Wilkinson MF, Joung JK. Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins. Nat Biotechnol 2013; 31:1137-42. PubMed
  • Mendenhall EM, Williamson KE, Reyon D, Zou JY, Ram O, Joung JK, Bernstein BE. Locus-specific editing of histone modifications at endogenous enhancers. Nat Biotechnol 2013; 31:1133-6. PubMed
  • Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, Kuscu C, Hricik T, Ndiaye-Lobry D, Lafave LM, Koche R, Shih AH, Guryanova OA, Kim E, Li S, Pandey S, Shin JY, Telis L, Liu J, Bhatt PK, Monette S, Zhao X, Mason CE, Park CY, Bernstein BE, Aifantis I, Levine RL. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med 2013; 210:2641-59. PubMed
  • Sander JD, Ramirez CL, Linder SJ, Pattanayak V, Shoresh N, Ku M, Foden JA, Reyon D, Bernstein BE, Liu DR, Joung JK. In silico abstraction of zinc finger nuclease cleavage profiles reveals an expanded landscape of off-target sites. Nucleic Acids Res 2013; 41:e181. PubMed
  • Isono K, Endo TA, Ku M, Yamada D, Suzuki R, Sharif J, Ishikura T, Toyoda T, Bernstein BE, Koseki H. SAM domain polymerization links subnuclear clustering of PRC1 to gene silencing. Dev Cell 2013; 26:565-77. PubMed
  • Ziller MJ, Gu H, Müller F, Donaghey J, Tsai LT, Kohlbacher O, De Jager PL, Rosen ED, Bennett DA, Bernstein BE, Gnirke A, Meissner A. Charting a dynamic DNA methylation landscape of the human genome. Nature 2013; 500:477-81. PubMed
  • Rheinbay E, Suvà ML, Gillespie SM, Wakimoto H, Patel AP, Shahid M, Oksuz O, Rabkin SD, Martuza RL, Rivera MN, Louis DN, Kasif S, Chi AS, Bernstein BE. An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep 2013; 3:1567-79. PubMed
  • Suvà ML, Riggi N, Bernstein BE. Epigenetic reprogramming in cancer. Science 2013; 339:1567-70. PubMed
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